Showing papers in "Cold Spring Harbor Perspectives in Medicine in 2015"
TL;DR: An examination of the PI3K-Akt and Ras-ERK pathways illustrates how such alterations dysregulate signaling in cancer and produce many of the characteristic features of tumor cells.
Abstract: Cancer is driven by genetic and epigenetic alterations that allow cells to overproliferate and escape mechanisms that normally control their survival and migration. Many of these alterations map to signaling pathways that control cell growth and division, cell death, cell fate, and cell motility, and can be placed in the context of distortions of wider signaling networks that fuel cancer progression, such as changes in the tumor microenvironment, angiogenesis, and inflammation. Mutations that convert cellular proto-oncogenes to oncogenes can cause hyperactivation of these signaling pathways, whereas inactivation of tumor suppressors eliminates critical negative regulators of signaling. An examination of the PI3K-Akt and Ras-ERK pathways illustrates how such alterations dysregulate signaling in cancer and produce many of the characteristic features of tumor cells.
597 citations
TL;DR: The clinical aspects of seizures and epilepsy are defined, diagnostic methods are reviewed, various clinical syndromes are discussed, and aspects of differential diagnosis, treatment, and prognosis are considered to enable neuroscientists to formulate basic and translational research questions.
Abstract: Epilepsy is one of the most common and disabling neurologic conditions, yet we have an incomplete understanding of the detailed pathophysiology and, thus, treatment rationale for much of epilepsy. This article reviews the clinical aspects of seizures and epilepsy with the goal of providing neuroscientists an introduction to aspects that might be amenable to scientific investigation. Seizures and epilepsy are defined, diagnostic methods are reviewed, various clinical syndromes are discussed, and aspects of differential diagnosis, treatment, and prognosis are considered to enable neuroscientists to formulate basic and translational research questions.
499 citations
TL;DR: This article will focus on the contribution of skin appendages to wound healing and, conversely, skin appendage regeneration following injuries.
Abstract: The skin is a complex organ consisting of the epidermis, dermis, and skin appendages, including the hair follicle and sebaceous gland. Wound healing in adult mammals results in scar formation without any skin appendages. Studies have reported remarkable examples of scarless healing in fetal skin and appendage regeneration in adult skin following the infliction of large wounds. The models used in these studies have offered a new platform for investigations of the cellular and molecular mechanisms underlying wound healing and skin regeneration in mammals. In this article, we will focus on the contribution of skin appendages to wound healing and, conversely, skin appendage regeneration following injuries.
389 citations
TL;DR: New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal drug resistance.
Abstract: As fatalities associated with fungal infections continue to grow as a major global health issue, the need for effective antifungal treatment is crucial. The current number of effective therapeutic drug options, however, is limited. With this, the documented rise in antifungal drug resistance in recent years is a critical concern, as resistance development severely limits the ability to successfully treat fatal infection. In this chapter, we explain the unique mechanisms of action of each antifungal drug class, including the polyenes, azoles, echinocandins, allylamines, flucytosine, griseofulvin, and potassium iodide. Furthermore, we discuss other mechanisms of resistance including biofilms, chromosomal abnormalities, and mitochondrial defects.
367 citations
TL;DR: Current knowledge regarding the decline of skin structure and function induced by the passage of time (chronological aging) and chronic exposure to solar UV irradiation (photoaging) are discussed.
Abstract: With worldwide expansion of the aging population, research on age-related pathologies is receiving growing interest. In this review, we discuss current knowledge regarding the decline of skin structure and function induced by the passage of time (chronological aging) and chronic exposure to solar UV irradiation (photoaging). Nearly every aspect of skin biology is affected by aging. The self-renewing capability of the epidermis, which provides vital barrier function, is diminished with age. Vital thermoregulation function of eccrine sweat glands is also altered with age. The dermal collagenous extracellular matrix, which comprises the bulk of skin and confers strength and resiliency, undergoes gradual fragmentation, which deleteriously impacts skin mechanical properties and dermal cell functions. Aging also affects wound repair, pigmentation, innervation, immunity, vasculature, and subcutaneous fat homeostasis. Altogether, age-related alterations of skin lead to age-related skin fragility and diseases.
330 citations
TL;DR: Cure is often possible with early identification of resistance and use of a properly designed regimen, and community-based programs can improve treatment outcomes by allowing patients to be treated in their homes and addressing socioeconomic barriers to adherence.
Abstract: The continuing spread of drug-resistant tuberculosis (TB) is one of the most urgent and difficult challenges facing global TB control. Patients who are infected with strains resistant to isoniazid and rifampicin, called multidrug-resistant (MDR) TB, are practically incurable by standard first-line treatment. In 2012, there were approximately 450,000 new cases and 170,000 deaths because of MDR-TB. Extensively drug-resistant (XDR) TB refers to MDR-TB strains that are resistant to fluoroquinolones and second-line injectable drugs. The main causes of the spread of resistant TB are weak medical systems, amplification of resistance patterns through incorrect treatment, and transmission in communities and facilities. Although patients harboring MDR and XDR strains present a formidable challenge for treatment, cure is often possible with early identification of resistance and use of a properly designed regimen. Community-based programs can improve treatment outcomes by allowing patients to be treated in their homes and addressing socioeconomic barriers to adherence.
329 citations
TL;DR: Few among the millions of fungal species fulfill four basic conditions necessary to infect humans: high temperature tolerance, ability to invade the human host, lysis and absorption of human tissue, and resistance to the human immune system.
Abstract: Few among the millions of fungal species fulfill four basic conditions necessary to infect humans: high temperature tolerance, ability to invade the human host, lysis and absorption of human tissue, and resistance to the human immune system. In previously healthy individuals, invasive fungal disease is rare because animals' sophisticated immune systems evolved in constant response to fungal challenges. In contrast, fungal diseases occur frequently in immunocompromised patients. Paradoxically, successes of modern medicine have put increasing numbers of patients at risk for invasive fungal infections. Uncontrolled HIV infection additionally makes millions vulnerable to lethal fungal diseases. A concerted scientific and social effort is needed to meet these challenges.
240 citations
TL;DR: The increased recognition of HBV infection as a leading cause of death globally has resulted in the development of new structures and policies at the international level; immediate attention to implementing these strategies is now required.
Abstract: The epidemiology of hepatitis B virus (HBV) infection is geographically diverse, with population prevalence, age and mode of acquisition, and likelihood of progression to chronic infection mutually interdependent. The burden of chronic HBV infection is increasingly being recognized, with cirrhosis and liver cancer attributable to HBV continuing to increase. The outcomes of chronic HBV infection are affected by a range of factors, including viral genotype, the presence of coinfections with other blood-borne viruses, and the impact of other causes of liver disease. The increased recognition of HBV infection as a leading cause of death globally has resulted in the development of new structures and policies at the international level; immediate attention to implementing these strategies is now required.
240 citations
TL;DR: Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age- related diseases and promoting a healthy life span.
Abstract: Aging in mammals is accompanied by a progressive atrophy of tissues and organs, and stochastic damage accumulation to the macromolecules DNA, RNA, proteins, and lipids. The sequence of the human genome represents our genetic blueprint, and accumulating evidence suggests that loss of genomic maintenance may causally contribute to aging. Distinct evidence for a role of imperfect DNA repair in aging is that several premature aging syndromes have underlying genetic DNA repair defects. Accumulation of DNA damage may be particularly prevalent in the central nervous system owing to the low DNA repair capacity in postmitotic brain tissue. It is generally believed that the cumulative effects of the deleterious changes that occur in aging, mostly after the reproductive phase, contribute to species-specific rates of aging. In addition to nuclear DNA damage contributions to aging, there is also abundant evidence for a causative link between mitochondrial DNA damage and the major phenotypes associated with aging. Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age-related diseases and promoting a healthy life span.
239 citations
TL;DR: Future efforts to manage the epileptic patient with glutamatergic-centric treatments now hold greater potential, as better understanding of this system has generated novel therapeutic targets that directly and indirectly modulate glutamatorgic signaling.
Abstract: Epilepsy is broadly characterized by aberrant neuronal excitability. Glutamate is the predominant excitatory neurotransmitter in the adult mammalian brain; thus, much of past epilepsy research has attempted to understand the role of glutamate in seizures and epilepsy. Seizures induce elevations in extracellular glutamate, which then contribute to excitotoxic damage. Chronic seizures can alter neuronal and glial expression of glutamate receptors and uptake transporters, further contributing to epileptogenesis. Evidence points to a shared glutamate pathology for epilepsy and other central nervous system (CNS) disorders, including depression, which is often a comorbidity of epilepsy. Therapies that target glutamatergic neurotransmission are available, but many have met with difficulty because of untoward adverse effects. Better understanding of this system has generated novel therapeutic targets that directly and indirectly modulate glutamatergic signaling. Thus, future efforts to manage the epileptic patient with glutamatergic-centric treatments now hold greater potential.
235 citations
TL;DR: This work focuses on reviewing the incidence, staging, and treatment of liver cancer, and there are variations in the management recommendations for liver cancers across specialties and geographic regions.
Abstract: Primary liver cancer, mostly hepatocellular carcinoma, remains a difficult-to-treat cancer. Incidence of liver cancer varies geographically and parallels with the geographic prevalence of viral hepatitis. A number of staging systems have been developed, reflecting the heterogeneity of primary liver cancer, regional preferences, and regional variations in resectability or transplant eligibility. Multimodality treatments are available for this heterogeneous malignancy, and there are variations in the management recommendations for liver cancers across specialties and geographic regions. Novel treatment strategies have merged with the advance of new treatment modalities. This work focuses on reviewing the incidence, staging, and treatment of liver cancer.
TL;DR: The clinical management of HIV-associated TB includes the integration of effective anti-TB treatment, use of concurrent antiretroviral therapy (ART), prevention of HIV -related comorbidities, management of drug cytotoxicity, and prevention/treatment of immune reconstitution inflammatory syndrome (IRIS).
Abstract: Tuberculosis (TB) and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) constitute the main burden of infectious disease in resource-limited countries. In the individual host, the two pathogens, Mycobacterium tuberculosis and HIV, potentiate one another, accelerating the deterioration of immunological functions. In high-burden settings, HIV coinfection is the most important risk factor for developing active TB, which increases the susceptibility to primary infection or reinfection and also the risk of TB reactivation for patients with latent TB. M. tuberculosis infection also has a negative impact on the immune response to HIV, accelerating the progression from HIV infection to AIDS. The clinical management of HIV-associated TB includes the integration of effective anti-TB treatment, use of concurrent antiretroviral therapy (ART), prevention of HIV-related comorbidities, management of drug cytotoxicity, and prevention/treatment of immune reconstitution inflammatory syndrome (IRIS).
TL;DR: This article presents estimates of TB incidence, prevalence, and mortality in 2012 and an assessment of progress toward the 2015 targets for reductions, and analyzes trends in TB notifications and in the implementation of the Stop TB Strategy.
Abstract: Tuberculosis has been present in the lives of human beings for many centuries. Evidence of bone lesions suggestive of tuberculosis in mummies of North America, Peru, and Egypt confirms the ancient impact of this disease on early civilizations (Rothschild et al. 2001; Nerlich et al. 2000; Salo et al. 1994). More than 50 years after the introduction of anti-tuberculosis chemotherapy, one-third of the world population is estimated to be infected with Mycobacterium tuberculosis and active disease remains a worldwide pandemic, with more than eight million new cases every year and almost two million deaths annually (Corbett et al. 2003). Despite the existence of a proven comprehensive cost-effective strategy-DOTS-aimed to reduce mortality, morbidity, and transmission of the disease, only 32% of the estimated new smearpositive tuberculosis cases worldwide were managed under this strategy in 2001. The emergence of the human immunodeficiency virus (HIV)/acquired immunodeficiency Syndrome (AIDS) and of multidrug-resistant tuberculosis (MDR-TB-resistance to at least isoniazid and rifampicin) have posed additional challenges to tuberculosis control. In order to accelerate control efforts and overcome these threats, partnership efforts by the international Community and a revised framework for tuberculosis control have been launched at the beginning of this new century. This chapter will review the epidemiology of infection and disease with M. tuberculosis globally, present morbidity and mortality data, discuss the impact of HIV and MDR-TB, and examine future trends.
TL;DR: Investigation of specimens from patients with pharmacoresistant temporal lobe epilepsy and epilepsy models revealed alterations in expression, localization, and function of astroglial K(+) and water channels, suggesting that dysfunctional astrocytes are crucial players in epilepsy and should be considered as promising targets for new therapeutic strategies.
Abstract: Astrocytes express ion channels, transmitter receptors, and transporters and, thus, are endowed with the machinery to sense and respond to neuronal activity. Recent studies have implicated that astrocytes play important roles in physiology, but these cells also emerge as crucial actors in epilepsy. Astrocytes are abundantly coupled through gap junctions allowing them to redistribute elevated K(+) and transmitter concentrations from sites of enhanced neuronal activity. Investigation of specimens from patients with pharmacoresistant temporal lobe epilepsy and epilepsy models revealed alterations in expression, localization, and function of astroglial K(+) and water channels. In addition, malfunction of glutamate transporters and the astrocytic glutamate-converting enzyme, glutamine synthetase, has been observed in epileptic tissue. These findings suggest that dysfunctional astrocytes are crucial players in epilepsy and should be considered as promising targets for new therapeutic strategies.
TL;DR: HBV genotypes and variants may serve as viral genetic markers to predict disease progression as well as help practicing physicians optimize individualized antiviral therapy in clinical practice.
Abstract: At least 10 hepatitis B virus (HBV) genotypes (A to J) with distinct geographic distributions and several HBV mutants, including precore/core promoter mutations and pre-S/S deletion mutations, have been recognized to be not only predictive of liver disease progression but also associated with response to antiviral therapy. HBV genotype-specific pathogenesis may contribute to heterogeneous clinical outcomes in chronic hepatitis B patients across the world. For example, patients with HBV genotypes C and D infection have a lower rate of spontaneous HBeAg seroconversion. In addition, HBV genotypes C and D have a higher frequency of core promoter and pre-S mutations than genotypes A and B. Genotypes C and D also carry a higher lifetime risk of cirrhosis and HCC development than genotypes A and B. Core promoter and pre-S mutations also correlate with an increased risk of hepatocellular carcinoma (HCC). Therapeutically, genotypes A and B patients have a better response to interferon-based therapy than genotypes C and D patients, but the response to nucleos(t)ide analogs is comparable across different HBV genotypes. In conclusion, HBV genotypes and variants may serve as viral genetic markers to predict disease progression as well as help practicing physicians optimize individualized antiviral therapy in clinical practice.
TL;DR: This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease.
Abstract: The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal.
TL;DR: Early diagnosis, species identification, and adequate antifungal therapy are key elements for treatment of the disease, especially in cases of pulmonary invasive aspergillosis that often advance very rapidly.
Abstract: The genus Aspergillus contains etiologic agents of aspergillosis. The clinical manifestations of the disease range from allergic reaction to invasive pulmonary infection. Among the pathogenic aspergilli, Aspergillus fumigatus is most ubiquitous in the environment and is the major cause of the disease, followed by Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Aspergillus nidulans, and several species in the section Fumigati that morphologically resemble A. fumigatus. Patients that are at risk for acquiring aspergillosis are those with an altered immune system. Early diagnosis, species identification, and adequate antifungal therapy are key elements for treatment of the disease, especially in cases of pulmonary invasive aspergillosis that often advance very rapidly. Incorporating knowledge of the basic biology of Aspergillus species to that of the diseases that they cause is fundamental for further progress in the field.
TL;DR: The microbial chemistry of this unique heteropolysacchride is explored, the molecular genetics that underpins its fabrication are examined, and how the essential biosynthetic process might be exploited for the development of future anti-TB chemotherapies are discussed.
Abstract: The mycobacterial bacillus is encompassed by a remarkably elaborate cell wall structure. The mycolyl-arabinogalactan-peptidoglycan (mAGP) complex is essential for the viability of Mycobacterium tuberculosis and maintains a robust basal structure supporting the upper "myco-membrane." M. tuberculosis peptidoglycan, although appearing to be unexceptional at first glance, contains a number of unique molecular subtleties that become particularly important as the TB-bacilli enters into nonreplicative growth during dormancy. Arabinogalactan, a highly branched polysaccharide, serves to connect peptidoglycan with the outer mycolic acid layer, and a variety of unique glycolsyltransferases are used for its assembly. In this review, we shall explore the microbial chemistry of this unique heteropolysacchride, examine the molecular genetics that underpins its fabrication, and discuss how the essential biosynthetic process might be exploited for the development of future anti-TB chemotherapies.
TL;DR: Although IRDs remain untreatable today, significant progress toward therapeutic strategies for IRDs has marked the past two decades, based on better understanding of the pathophysiological pathways of these diseases and on technological advances.
Abstract: Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2 million people worldwide) (Bessant DA, Ali RR, Bhattacharya SS. 2001. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev 11: 307-316.). IRDs may be inherited as Mendelian traits or through mitochondrial DNA, and may affect the entire retina (e.g., rod-cone dystrophy, also known as retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, choroideremia, Usher syndrome, and Bardet-Bidel syndrome) or be restricted to the macula (e.g., Stargardt disease, Best disease, and Sorsby fundus dystrophy), ultimately leading to blindness. IRDs are a major cause of severe vision loss, with profound impact on patients and society. Although IRDs remain untreatable today, significant progress toward therapeutic strategies for IRDs has marked the past two decades. This progress has been based on better understanding of the pathophysiological pathways of these diseases and on technological advances.
TL;DR: This work describes recent insights in understanding the mammalian immune defenses that are deployed against pathogenic fungi and creates a foundation for the development of new, immune-based strategies for prevention or enhanced clearance of systemic fungal diseases.
Abstract: Life-threatening fungal infections have risen sharply in recent years, owing to the advances and intensity of medical care that may blunt immunity in patients. This emerging crisis has created the growing need to clarify immune defense mechanisms against fungi with the ultimate goal of therapeutic intervention. We describe recent insights in understanding the mammalian immune defenses that are deployed against pathogenic fungi. We focus on adaptive immunity to the major medically important fungi and emphasize three elements that coordinate the response: (1) dendritic cells and subsets that are mobilized against fungi in various anatomical compartments; (2) fungal molecular patterns and their corresponding receptors that signal responses and shape the differentiation of T-cell subsets and B cells; and, ultimately (3) the effector and regulatory mechanisms that eliminate these invaders while constraining collateral damage to vital tissue. These insights create a foundation for the development of new, immune-based strategies for prevention or enhanced clearance of systemic fungal diseases.
[...]
TL;DR: An overview of the phenotypic changes of cardiac aging, the molecular mechanisms underlying these changes, and some of the recent advances in the development of interventions to delay or reverse cardiac aging are presented.
Abstract: Aging results in progressive deteriorations in the structure and function of the heart and is a dominant risk factor for cardiovascular diseases, the leading cause of death in Western populations. Although the phenotypes of cardiac aging have been well characterized, the molecular mechanisms of cardiac aging are just beginning to be revealed. With the continuously growing elderly population, there is a great need for interventions in cardiac aging. This article will provide an overview of the phenotypic changes of cardiac aging, the molecular mechanisms underlying these changes, and will present some of the recent advances in the development of interventions to delay or reverse cardiac aging.
TL;DR: Adding one or several new drugs to current regimens should offer the prospect of markedly improving the response to therapy, thus reducing the burden of drug resistance, as well as the incidence of cirrhosis and hepatocellular carcinoma.
Abstract: Current therapies of chronic hepatitis B (CHB) remain limited to either pegylated interferon-α (Peg-IFN-α), or one of the five approved nucleoside analog (NA) treatments. Although viral suppression can be achieved in the majority of patients with high-barrier-to-resistance new-generation NAs (i.e., entecavir and tenofovir), HBsAg loss is achieved in only 10% of patients with both classes of drugs after a follow-up of 5 years. Attempts to improve the response by administering two different NAs or a combination of NA and Peg-IFN-α have been unsuccessful. Therefore, there is a renewed interest to investigate a number of steps in the hepatitis B virus (HBV) replication cycle and specific virus-host cell interactions as potential targets for new antivirals. Novel targets and compounds could readily be evaluated using both relevant in vitro and newly developed in vivo models of HBV infection. The addition of one or several new drugs to current regimens should offer the prospect of markedly improving the response to therapy, thus reducing the burden of drug resistance, as well as the incidence of cirrhosis and hepatocellular carcinoma (HCC).
TL;DR: New antituberculosis drugs (bedaquiline and delamanid) have been recently approved by the health authorities, but they cannot represent the definitive solution to the clinical management of drug-resistant tuberculosis forms, particularly in intermediate economy settings where the prevalence of drug resistance is high.
Abstract: Tuberculosis is an airborne infectious disease treated with combination therapeutic regimens. Adherence to long-term antituberculosis therapy is crucial for maintaining adequate blood drug level. The emergence and spread of drug-resistant Mycobacterium tuberculosis strains are mainly favored by the inadequate medical management of the patients. The therapeutic approach for drug-resistant tuberculosis is cumbersome, because of the poor, expensive, less-effective, and toxic alternatives to the first-line drugs. New antituberculosis drugs (bedaquiline and delamanid) have been recently approved by the health authorities, but they cannot represent the definitive solution to the clinical management of drug-resistant tuberculosis forms, particularly in intermediate economy settings where the prevalence of drug resistance is high (China, India, and former Soviet Union countries). New research and development activities are urgently needed. Public health policies are required to preserve the new and old therapeutic options.
TL;DR: The successful clinical trials of gene augmentation therapy for Retinal degeneration caused by mutations in the RPE65 gene sets the stage for broad application of gene therapy to treat retinal degenerative disorders.
Abstract: Several groups have reported the results of clinical trials of gene augmentation therapy for Leber congenital amaurosis (LCA) because of mutations in the RPE65 gene These studies have used subretinal injection of adeno-associated virus (AAV) vectors to deliver the human RPE65 cDNA to the retinal pigment epithelial (RPE) cells of the treated eyes In all of the studies reported to date, this approach has been shown to be both safe and effective The successful clinical trials of gene augmentation therapy for retinal degeneration caused by mutations in the RPE65 gene sets the stage for broad application of gene therapy to treat retinal degenerative disorders
TL;DR: Control of hepatitis B virus (HBV) in the last two decades has consistently diminished the circulation of HDV in industrialized countries, however, hepatitis D remains a medical issue for injecting drug users (IDUs), as well as immigrants from endemic HDV areas, who are reintroducing the infection in Europe.
Abstract: Hepatitis D is caused by the hepatitis D virus (HDV), a unique RNA pathogen that requires the hepatitis B surface antigen (HBsAg) to infect. Hepatitis D is transmitted by the parenteral route. The main susceptible group is patients with chronic HBsAg infection who become superinfected with the virus. Hepatitis D occurs throughout the globe, but control of hepatitis B virus (HBV) in the last two decades has consistently diminished the circulation of HDV in industrialized countries. However, hepatitis D remains a medical issue for injecting drug users (IDUs), as well as immigrants from endemic HDV areas, who are reintroducing the infection in Europe.
TL;DR: In addition to identifying the cause of disease in the remaining 25% of adRP families, a central challenge is reconciling clinical diagnosis, family history, and molecular findings in patients and families.
Abstract: Retinitis pigmentosa (RP) has a prevalence of approximately one in 4000; 25%-30% of these cases are autosomal dominant retinitis pigmentosa (adRP). Like other forms of inherited retinal disease, adRP is exceptionally heterogeneous. Mutations in more than 25 genes are known to cause adRP, more than 1000 mutations have been reported in these genes, clinical findings are highly variable, and there is considerable overlap with other types of inherited disease. Currently, it is possible to detect disease-causing mutations in 50%-75% of adRP families in select populations. Genetic diagnosis of adRP has advantages over other forms of RP because segregation of disease in families is a useful tool for identifying and confirming potentially pathogenic variants, but there are disadvantages too. In addition to identifying the cause of disease in the remaining 25% of adRP families, a central challenge is reconciling clinical diagnosis, family history, and molecular findings in patients and families.
TL;DR: The role of key circulating antiangiogenic factors as pathogenic biomarkers and in the development of novel therapies for preeclampsia are highlighted.
Abstract: Preeclampsia is a pregnancy-specific disease characterized by new onset hypertension and proteinuria after 20 wk of gestation. It is a leading cause of maternal and fetal morbidity and mortality worldwide. Exciting discoveries in the last decade have contributed to a better understanding of the molecular basis of this disease. Epidemiological, experimental, and therapeutic studies from several laboratories have provided compelling evidence that an antiangiogenic state owing to alterations in circulating angiogenic factors leads to preeclampsia. In this review, we highlight the role of key circulating antiangiogenic factors as pathogenic biomarkers and in the development of novel therapies for preeclampsia.
TL;DR: Although it is widely believed that structural alterations induced by hyperactivated mTOR signaling are critical for epileptogenesis, newer evidence suggests that mTOR activation on its own may enhance neuronal excitability.
Abstract: Over the past decade enhanced activation of the mammalian target of rapamycin (mTOR)-signaling cascade has been identified in focal malformations of cortical development (MCD) subtypes, which have been collectively referred to as "mTORopathies." Mutations in mTOR regulatory genes (e.g., TSC1, TSC2, AKT3, DEPDC5) have been associated with several focal MCD highly associated with epilepsy such as tuberous sclerosis complex (TSC), hemimegalencephaly (HME; brain malformation associated with dramatic enlargement of one brain hemisphere), and cortical dysplasia. mTOR plays important roles in the regulation of cell division, growth, and survival, and, thus, aberrant activation of the cascade during cortical development can cause dramatic alterations in cell size, cortical lamination, and axon and dendrite outgrowth often observed in focal MCD. Although it is widely believed that structural alterations induced by hyperactivated mTOR signaling are critical for epileptogenesis, newer evidence suggests that mTOR activation on its own may enhance neuronal excitability. Clinical trials with mTOR inhibitors have shown efficacy in the treatment of seizures associated with focal MCD.
TL;DR: The current state of knowledge on the mechanisms of hepadnavirus reverse transcription and the biochemical and structural properties of the viral reverse transcriptase (RT) are summarized and important gaps in knowledge regarding cccDNA biosynthesis and stability are highlighted.
Abstract: Hallmarks of the hepadnavirus replication cycle are the formation of covalently closed circular DNA (cccDNA) and the reverse transcription of a pregenomic RNA (pgRNA) in core particles leading to synthesis of the relaxed circular DNA (rcDNA) genome. cccDNA, the template for viral RNA transcription, is the basis for the persistence of these viruses in infected hepatocytes. In this review, we summarize the current state of knowledge on the mechanisms of hepadnavirus reverse transcription and the biochemical and structural properties of the viral reverse transcriptase (RT). We highlight important gaps in knowledge regarding cccDNA biosynthesis and stability. In addition, we discuss the impact of current antiviral therapies on viral persistence, particularly on cccDNA.
TL;DR: Despite numerous treatments available to control repetitive seizures, a large percentage of patients continue to suffer the consequences of uncontrolled seizures, which include psychosocial stigma and death.
Abstract: Epilepsy, a disorder of unprovoked seizures is a multifaceted disease affecting individuals of all ages with a particular predilection for the very young and old. In addition to seizures, many patients often report cognitive and psychiatric problems associated with both the seizures themselves and its therapy. Epilepsy has numerous etiologies both idiopathic and acquired with a wide range of therapeutic responses. Despite numerous treatments available to control repetitive seizures including medications, diets, immunotherapy, surgery, and neuromodulatory devices, a large percentage of patients continue to suffer the consequences of uncontrolled seizures, which include psychosocial stigma and death.